Synaptic function of BK channel-interacting proteins

阿尔茨海默氏病（AD）是一种神经退行性疾病，困扰着许多人。大多数早发性 家族性AD与早老素的突变有关。以前对早老素的研究主要集中在它们在 β淀粉样蛋白（Aβ）的产生，因为Aβ斑块在脑组织中的积累通常被认为是 AD的主要原因然而，淀粉样蛋白假说正受到质疑，因为所有抗淀粉样蛋白的临床试验 失败了因此，有必要探讨早老素在AD中的其他潜在作用机制。之间 早老素突变的已知作用是减少神经递质释放和钙稳态失调， 这两者都是AD的假定潜在机制。已知早老素的突变引起减少的 神经递质释放和钙稳态失调，这与 Ryanodine受体表达降低。然而，尚不清楚早老素如何调节兰尼碱受体。 本研究旨在验证早老素通过以下途径调节兰尼碱受体表达的假说： 一些其他的调节蛋白。以秀丽隐杆线虫为动物模型， 由于哺乳动物系统中的许多细胞机制， 早老素在突触和ryanodine受体功能中的作用在蠕虫中是保守的。具体目标是 建议是：1）通过质量鉴定推定的兰尼碱受体表达调节蛋白的候选物 光谱法和RNA测序，以及2）确定所鉴定的蛋白质是否是早老素作用所需的 神经递质释放和ryanodine受体表达。我们的长期目标是说明， 神经递质释放减少和兰尼碱受体功能在AD发病机制中的作用 是由早老素突变引起的

Alzheimer’s disease (AD) is a neurodegenerative disorder inflicting many people. Most cases of early-onset familial AD are linked to mutations of presenilins. Previous studies on presenilins have focused on their roles in the generation of amyloid β (Aβ) because accumulation of Aβ plaques in brain tissue is generally considered the primary cause of AD. However, the amyloid hypothesis is being questioned because all anti-amyloid clinical trials have failed. Therefore, it is necessary to explore other potential mechanisms of presenilin function in AD. Among the known effects of presenilin mutations are reduced neurotransmitter release and calcium dyshomeostasis, which are both putative underlying mechanisms of AD. It is known that mutations of presenilins cause reduced neurotransmitter release and calcium dyshomeostasis, which are associated with and potentially caused by decreased ryanodine receptor expression. However, it is unknown how presenilins regulate ryanodine receptors. This proposal is to test the hypothesis that presenilins regulate ryanodine receptor expression by acting through some other regulatory proteins. The nematode Caenorhabditis elegans is used as an animal model to identify the putative regulatory proteins because many cellular mechanisms in mammalian systems, including the roles of presenilins in synaptic and ryanodine receptor function, are conserved in worms. The specific aims of this proposal are: 1) identify candidates for the putative regulatory proteins of ryanodine receptor expression by mass spectrometry and RNA-seq, and 2) determine whether the identified proteins are required for presenilins’ roles in neurotransmitter release and ryanodine receptor expression. Our long-term goal is to illustrate whether and how reduced neurotransmitter release and ryanodine receptor function play a role in the pathogenesis of AD caused by presenilin mutations.